Mechanisms of Isocyanate Induced Airways Hyperreactivity. This investigation will study mechanims to explain isocyanate induced airways reactivity. We propose that TDI affects bronchial mucosal permeability perhaps by altering the tight junction between cells. This allows movement of environmental agents across the barrier causing more intimate contact with smooth muscle, mucous glands, mast cells and irritant nerve endings located beneath the barrier. Degranulation of mast cells results in release of vasoactive mediators and resultant airways effects. Smooth muscle contraction and mucous gland secretion may be the result of direct irritant nature of TDI. TDI may also affect beta-adrenergic function of cells leading to reduced intracellular levels of cAMP and potentiation of mast cell degranulation and smooth muscle contraction. Increased sensitivity to histamine aerosol occurs either because there is more direct sensitization of irritant nerve receptors or because there is more direct access to the receptors. We plan to test this hypothesis by exposing guinea pigs to several different concentrations of TDI and performing tests to: 1) determine the status of bronchial mucosal permeability by monitoring the movement of labeled HRP from airways lumen to blood; 2) document airway reactivity to inhaled histamine aerosol; 3) meausre beta-adrenergic function of lung tissue by adenylate cyclase assays and beta adrenergic receptor binding studies; and 4) record and quantitate serial ultrastructural changes in airways. Information gained in this investigation may provide a better understanding of occupational airways disease due to TDI.